PROJECT SUMMARY The success of prostate cancer (PCa) therapies with the goal of improving overall survival principally hinges on our ability to treat metastatic disease as shown by the sharp decline of 5-year survival rates from 100% in localized and regional disease to <30% in metastatic disease. Docetaxel and platinum-based drugs have been the first-line chemotherapy for metastatic castration-resistant prostate cancer (mCRPC) for many years, however, the survival benefit of docetaxel and platinum-based drugs is modest and patients inevitably develop resistance. Therefore, improving the efficacy of docetaxel and carboplatin and preventing or reversing docetaxel and carboplatin resistance of mCRPC, especially those in the bone, would have a large impact on improving overall survival of men with mCRPC. The receptor tyrosine kinase AXL has been identified as a key molecule in resistance to both conventional chemotherapy and targeted therapies. In PCa, AXL is an essential regulator of cell proliferation, migration, invasion and docetaxel resistance. In addition, AXL inhibition sensitized mCRPC cells to docetaxel when grown at the subcutaneous site, suggesting that AXL inhibition may be an effective strategy to reverse docetaxel resistance in mCRPC. We propose to determine whether blocking AXL signaling using a novel soluble AXL (sAXL) decoy receptor will inhibit mCPRC growth in the bone, which produce the greatest morbidity due to fractures, bone pain, and spinal cord compression, as a single agent and whether this decoy receptor will sensitize cancer cells to docetaxel or carboplatin when used in combination. This decoy receptor has shown excellent efficacy with little toxicity in inhibiting tumor growth and reverse drug resistance and currently being evaluated in clinical trials in other cancer types. To enhance rapid translation of our findings to the clinic, we will use the most clinically relevant bone models of mCRPC generated by direct implantation of patient-derived xenograft (PDX) tissues into mice. We will select 4 out of the 12 available castration-resistant PDX models to test sAXL therapy in this study. Moreover, we will identify biomarkers that predict responses to this inhibitor by comparing the gene expression profiles of tumors responding to treatments to those that do not at RNA and protein levels. Our study represents the first attempt to evaluate whether inhibition of tyrosine kinase receptor AXL in mCRPC will be effective in suppressing tumor growth in the bone. If our small preclinical scale study demonstrates efficacy of sAXL as a single agent or in synergy with docetaxel and carboplatin in treating mCRPC, we will have compelling evidence for testing of sAXL therapy in a much larger study using all 12 castration-resistant PDX lines. Our long-term goal is to provide strong rationale for a phase 2 clinical trial of sAXL therapy in men with mCRPC.